The long term goals of this proposal are: 1) to elucidate the mechanisms and the regulation of the fusion of mononuclear phagocytes (MNP) leading to the formation of both osteoclasts and giant cells. 2) to characterize the functional consequences of multinucleation in both normal and pathological bone resorption and in the host defense mechanisms involved in inflammatory reactions and tumors. The strategy adopted to reach these goals is based on the simultaneous use of two approaches which complement each other: 1) the first approach focuses upon the cellular and molecular basis for the particular tendency of cells of the MNP lineage to form polykaryons. This approach will more specifically involve the detection, the characterization and the kinetic analysis of new plasma membrane and soluble antigens. 2) the second approach focuses upon the role of the local microenvironment in the induction and the regulation of the fusion mechanism of the mononuclear precursors (MNP). Both agonist and antagonist factors will be searched for and analyzed. These two approaches closely interact in that the effects of local factors on the plasma membrane protein composition will also be studied. Parallel studies will be continued on in vivo induced osteoclasts and giant cells analyzing and comparing their respective antigenic determinants using immunoelectron microscopy techniques. In the long run, these studies may be of critical importance in the understanding of the functional implications of macrophage fusion is bone resorption and host defense mechanisms.